Myosin Isoform-Dependent Effect of Omecamtiv Mecarbil on the Regulation of Force Generation in Human Cardiac Muscle.

Omecamtiv mecarbil (OM) is a small molecule that has been shown to improve the function of the slow human ventricular myosin (MyHC) motor through a complex perturbation of the thin/thick filament regulatory state of the sarcomere mediated by binding to myosin allosteric sites coupled to inorganic phosphate (Pi) release. Here, myofibrils from samples of human left ventricle (ß-slow MyHC-7) and left atrium (α-fast MyHC-6) from healthy donors were used to study the differential effects of µmolar [OM] on isometric force in relaxing conditions (pCa 9.0) and at maximal (pCa 4.5) or half-maximal (pCa 5.75) calcium activation, both under control conditions (15 °C; equimolar DMSO; contaminant inorganic phosphate [Pi] ~170 µM) and in the presence of 5 mM [Pi]. The activation state and OM concentration within the contractile lattice were rapidly altered by fast solution switching, demonstrating that the effect of OM was rapid and fully reversible with dose-dependent and myosin isoform-dependent features. In MyHC-7 ventricular myofibrils, OM increased submaximal and maximal Ca2+-activated isometric force with a complex dose-dependent effect peaking (40% increase) at 0.5 µM, whereas in MyHC-6 atrial myofibrils, it had no effect or-at concentrations above 5 µM-decreased the maximum Ca2+-activated force. In both ventricular and atrial myofibrils, OM strongly depressed the kinetics of force development and relaxation up to 90% at 10 µM [OM] and reduced the inhibition of force by inorganic phosphate. Interestingly, in the ventricle, but not in the atrium, OM induced a large dose-dependent Ca2+-independent force development and an increase in basal ATPase that were abolished by the presence of millimolar inorganic phosphate, consistent with the hypothesis that the widely reported Ca2+-sensitising effect of OM may be coupled to a change in the state of the thick filaments that resembles the on-off regulation of thin filaments by Ca2+. The complexity of this scenario may help to understand the disappointing results of clinical trials testing OM as inotropic support in systolic heart failure compared with currently available inotropic drugs that alter the calcium signalling cascade.

The Structure of Acto-Myosin.

After several decades studying different acto-myosin complexes at lower and intermediate resolution - limited by the electron microscope instrumentation available then - recent advances in imaging technology have been crucial for obtaining a number of excellent high-resolution 3D reconstructions from cryo electron microscopy. The resolution level reached now is about 3-4 Å, which allows unambiguous model building of filamentous actin on its own as well as that of actin filaments decorated with strongly bound myosin variants. The interface between actin and the myosin motor domain can now be described in detail, and the function of parts of the interface (such as, e.g., the cardiomyopathy loop) can be understood in a mechanistical way. Most recently, reconstructions of actin filaments decorated with different myosins, which show a strongly bound acto-myosin complex also in the presence of the nucleotide ADP, have become available. The comparison of these structures with the nucleotide-free Rigor state provide the first mechanistic description of force sensing. An open question is still the initial interaction of the motor domain of myosin with the actin filament. Such weakly interacting states have so far not been the subject of microscopical studies, even though high-resolution structures would be needed to shed light on the initial steps of phosphate release and power stroke initiation.

Force and Collective Epithelial Activities.

Cells apply forces to their surroundings to perform basic biological activities, including division, adhesion, and migration. Similarly, cell populations in epithelial tissues coordinate forces in physiological processes of morphogenesis and repair. These activities are highly regulated to yield the correct development and function of the body. The modification of this order is at the onset of pathological events and malfunctions. Mechanical forces and their translation into biological signals are the focus of an emerging field of research, shaping as a central discipline in the study of life and gathering knowledge at the interface of engineering, physics, biology and medicine. Novel engineering methods are needed to complement the classic instruments developed by molecular biology, physics and medicine. These should enable the measurement of forces at the cellular and multicellular level, and at a temporal and spatial resolution which is fully compatible with the ranges experienced by cells in vivo.

Cell and tissue mechanics in cell migration.

Migrating cells generate traction forces to counteract the movement-resisting forces arising from cell-internal stresses and matrix adhesions. In the case of collective migration in a cell colony, or in the case of 3-dimensional migration through connective tissue, movement-resisting forces arise also from external stresses. Although the deformation of a stiffer cell or matrix causes larger movement-resisting forces, at the same time a larger stiffness can also promote cell migration due to a feedback between forces, deformations, and deformation speed that is mediated by the acto-myosin contractile machinery of cells. This mechanical feedback is also important for stiffness sensing, durotaxis, plithotaxis, and collective migration in cell colonies.

ActO, a positive cluster-situated regulator for actinomycins biosynthesis in Streptomyces antibioticus ZS.

Actinomycins are a class of cyclic lipopeptide antibiotics produced by Streptomyces, which have rich biological activities and demonstrate great potential value. Among them, actinomycin D is currently the effective drug for some malignant tumor diseases. Although the chemical properties, biological activities and biosynthesis of actinomycins have been extensively studied, the regulation of their biosynthesis remains poorly understood. Streptomyces antibioticus ZS isolated from deep-sea corals is a producer of actinomycin D and actinomycin V. Here, we reported the characterization of a cluster-situated regulator ActO in actinomycins biosynthetic gene cluster (act cluster) of S. antibioticus ZS, which belongs to LmbU family. Deletion of actO completely blocked the synthesis of actinomycins. Overexpression of actO increased the yields of actinomycin D and actinomycin V by 4.4 fold and 2.6 fold, respectively. The result of RT-qPCR showed that ActO activates the transcription of all genes in act cluster. However, no specific binding of His6-ActO to the promoters of target genes was observed after electrophoretic mobility shift assay (EMSA). These results proved that ActO serves as a positive regulator involved in the biosynthesis of actinomycins, affecting the transcription of all genes related to the synthesis of intermediates, skeleton modification and extracellular transportation of final products. Moreover, we demonstrated that overexpression of actO is a novel strategy to increase the yields of actinomycins.

[Liver enzymes elevation: etiologic study and efficiency of a single-act office visit]. / Elevación de las enzimas de función hepática en nuestro medio: estudio etiológico y de la eficacia de una consulta de acto único.

BACKGROUND: Liver enzyme (LE) elevation is a common finding in routine blood analysis. There is very little information on the most prevalent causes of these alterations in our population. In addition, a number of tests and several visits to the specialist are required to reach a diagnosis. For these reasons, we designed a protocol to streamline the evaluation of patients with LE elevations in a single-act office visit. METHODS: From March 2008 until June 2010, we studied all patients with incidental LE elevation (isolated transaminase elevation, combined elevation of alkaline phosphatase [FA] and gamma-glutamyl transpeptidase [GGT], or isolated elevation of GGT) who were referred by their primary care physicians. At the time of referral, a complete biochemistry analysis was performed (LE, viral serology, autoantibodies, ceruloplasmin, iron metabolism, alpha-1-antitrypsin and thyroid hormones) and the patients underwent an abdominal ultrasound scan on the day of the office evaluation by the hepatologist. RESULTS: A total of 427 patients were included in our study. The most common cause of transaminase elevation was non-alcoholic fatty liver disease (NAFLD) (40%), followed by alcohol intake (17%), and hepatitis C virus infection (13%). Elevated GGT levels were most commonly related to NAFLD (30%), closely followed by alcohol intake (27%), and hepatotoxicity (8%). Combined elevation of GGT and FA was associated with NAFLD (21%), alcohol (17%), and hepatotoxicity (11%). Self-limited elevation was seen in 9% of the patients and we could not identify a definite cause in 11%. A definitive diagnosis was reached in 79% of the patients. CONCLUSIONS: The single-act office visit has proven to be efficient, yielding a diagnosis in most of the patients. The most common cause of elevated LE was NAFLD. Transaminase elevation must be confirmed before a more thorough work-up is started.

Cell-to-Cell Connectivity Assays for the Analysis of Cytoskeletal and Other Regulators of Plasmodesmata.

The actin cytoskeleton has close but so far incompletely understood connections to plasmodesmata, the cell junctions of plants. Plasmodesmata are essential for plant development and responses to biotic and abiotic stresses and facilitate the intercellular exchange of metabolites and hormones but also macromolecules such as proteins and RNAs. The molecular size exclusion limited of plasmodesmata is dynamically regulated, including by actin-associated proteins. Therefore, experimental analysis of plasmodesmal regulation can be relevant to plant cytoskeleton research. This chapter presents two simple imaging-based protocols for analyzing macromolecular cell-to-cell connectivity in leaves.

Adhesion strength and contractility enable metastatic cells to become adurotactic.

Significant changes in cell stiffness, contractility, and adhesion, i.e., mechanotype, are observed during a variety of biological processes. Whether cell mechanics merely change as a side effect of or driver for biological processes is still unclear. Here, we sort genotypically similar metastatic cancer cells into strongly adherent (SA) versus weakly adherent (WA) phenotypes to study how contractility and adhesion differences alter the ability of cells to sense and respond to gradients in material stiffness. We observe that SA cells migrate up a stiffness gradient, or durotax, while WA cells largely ignore the gradient, i.e., adurotax. Biophysical modeling and experimental validation suggest that differences in cell migration and durotaxis between weakly and strongly adherent cells are driven by differences in intra-cellular actomyosin activity. These results provide a direct relationship between cell phenotype and durotaxis and suggest how, unlike other senescent cells, metastatic cancer cells navigate against stiffness gradients.

V for versatility: TRPV4 Ca2+ entry channel plays multiple roles in invadosome regulation.

Several Ca2+-permeable cation channels attract attention for their mechanotransducer function to evoke Ca2+ signals in cell invasion. Vellino et al., have clarified the versatility of the osmo-sensing TRPV4 channel in regulating invadosome functions: TRPV4 detects and integrates multiple cellular and environmental cues, triggering Ca2+ signals and molecular interactions that modulate coupling between acto-adhesion and extracellular matrix degradation.

High capacity of ultrasound for locating parathyroid adenomas in endocrinology (the ETIEN 4 study). / Elevada capacidad de localización ecográfica de adenomas paratiroideos en endocrinología (estudio ETIEN 4).

OBJECTIVE: To assess the diagnostic performance of neck ultrasound examination performed by endocrinologists to locate parathyroid adenomas in patients with primary hyperparathyroidism (PHPT). METHODOLOGY: A retrospective observational study in 135 patients (mean age, 60.0±12.3 years; 74.8% females) seen at endocrinology for PHPT (mean calcium level, 11.3±1.2mg/dL mean PTH level, 240.4±346.8pg/mL) who underwent neck ultrasound examinations at the endocrinology department. 99mTc-MIBI parathyroid scintigraphy was performed before surgery in all patients. Sensitivity, specificity, positive predictive value, and negative predictive value were calculated in surgical patients. RESULTS: Ninety-eight patients underwent surgery for PHPT and 97.8% were cured at 6 months. Parathyroid ultrasound had a sensitivity of 85% (95% CI: 75.7%-91.2%) and a positive predictive value (PPV) of 95.2% (95% CI: 87.5%-98.4%) to locate parathyroid adenomas 1.7±0.9cm in maximum diameter (69.4% in smaller glands), showing a high correlation (r=0.661 and r=0.716) with maximum diameter and volume of the excised adenoma. Sixty percent of patients had nodular thyroid disease (64.2% bilateral nodules with mean maximum diameter of 1.5±0.9cm), and thyroidectomy was performed in 31.6%. The highest diagnostic performance was seen with a combination of neck ultrasound and 99mTc-MIBI scintigraphy (sensitivity: 96.8% and PPV: 95.8%). CONCLUSION: In our area, parathyroid adenoma localization with ultrasound performed by endocrinologists has a high diagnostic yield and allows for detecting nodular thyroid disease in 60% of patients.

A new standardised nomenclature in ophthalmology: Criteria and quantitative evaluation indicators of medical procedures. / Nuevo nomenclátor estandarizado en oftalmología: Criterios e indicadores cuantitativos de baremación de actos médicos.

PURPOSE: To create a new list of medical procedures in ophthalmology based on the International Classification of Diseases ICD-9-CM. To establish the general principles that define criteria, quantitative indicators, and scales. To develop the algorithms needed to calculate fees for medical procedures. METHODS: The out-of-date processes were removed from the list, and new techniques were added, descriptors were modified, procedures with similar descriptions were grouped together, and others were relocated to other group according to surgical complexity conditions. The criteria to calculate the medical fees were defined: training and complexity (U), proficient responsibility (R), and health value (V), with their respective quantitative indicators: period of training necessary to master a technique, frequency of complications that worsen the preoperative situation, and days of incapacity for work due to the process. The Relative Value Unit (RVU) was defined as the score sum of R, V and U. The final fee per medical procedure was calculated as the product of the RVU by its unit cost and by the weighting coefficient (WC). RESULTS: A new catalogue was prepared with 161 medical procedures, grouped into consultations, diagnostic procedures (DX.PR), therapeutic procedures (TX.PR), and surgical interventions, increasing in complexity from group 0 to group 8. The following characters were described for each one of the procedures: OMC and ICD-9-MC code, descriptor term, group, proposed modification: no changes or minimums in the descriptors, grouping of acts by similar definitions, change of origin group, new procedures, and procedures removed. The indicators for assessment were also scored: U between 1-4 points, and R and V between 0-3 points. Using their sum, the number of RVUs per medical procedure (between 1 and 10) was calculated which, together with the unit cost of the RVU and the WC (between 0.05 and 1), will determine the final rate. CONCLUSIONS: The new standardised ophthalmological nomenclature updates and improves the old classification, adapting the procedures to the descriptors included in the ICD-9-CM, and incorporating all the new techniques. Additionally, the declaration of the general principles allows defining new criteria, quantitative indicators, rating scales, and algorithms to calculate fees for medical procedures.

Efecto psicoterapéutico del acto médico / Psychotherapeutic effect of the medical act

Las personas que enferman expresan en su sufrimiento el desequilibrio de la armonía bio-psicosocial propia de la existencia humana. Por esto, la formación de los nuevos médicos no debe descuidar el sentido universal, integral, que debe tener esa educación superior. Este camino es el único que puede proteger a la profesión médica del riesgo grave de dejar de ser una formación universitaria, es decir abarcativa del todo, para quedar rebajada a la adquisición de conocimientos meramente técnicos que atiendan a una sola de las partes. De predominar lo técnico sobre lo humano, será cada vez más fácil que la Medicina quede a cargo de máquinas inteligentes y el hombre pierda definitivamente contacto con el hombre

"People who get sick suffer the imbalance of the bio-psico-social harmony of human existence. For this reason, the training of new doctors must not neglect the universal, integral sense that that higher education must have. This path is the only one that can protect the medical profession from the serious risk of ceasing to be part of a formal and comprehensive university training, to be reduced to the acquisition of purely technical knowledge that attends to only one of the parties involved. If the technical predominates over the human, it will be increasingly easy for Medicine to be in control of intelligent machines, and man will definitively lose contact with man"

p190RhoGAPs, the ARHGAP35- and ARHGAP5-Encoded Proteins, in Health and Disease.

Small guanosine triphosphatases (GTPases) gathered in the Rat sarcoma (Ras) superfamily represent a large family of proteins involved in several key cellular mechanisms. Within the Ras superfamily, the Ras homolog (Rho) family is specialized in the regulation of actin cytoskeleton-based mechanisms. These proteins switch between an active and an inactive state, resulting in subsequent inhibiting or activating downstream signals, leading finally to regulation of actin-based processes. The On/Off status of Rho GTPases implicates two subsets of regulators: GEFs (guanine nucleotide exchange factors), which favor the active GTP (guanosine triphosphate) status of the GTPase and GAPs (GTPase activating proteins), which inhibit the GTPase by enhancing the GTP hydrolysis. In humans, the 20 identified Rho GTPases are regulated by over 70 GAP proteins suggesting a complex, but well-defined, spatio-temporal implication of these GAPs. Among the quite large number of RhoGAPs, we focus on p190RhoGAP, which is known as the main negative regulator of RhoA, but not exclusively. Two isoforms, p190A and p190B, are encoded by ARHGAP35 and ARHGAP5 genes, respectively. We describe here the function of each of these isoforms in physiological processes and sum up findings on their role in pathological conditions such as neurological disorders and cancers.

Contractile acto-myosin network on nuclear envelope remnants positions human chromosomes for mitosis.

To ensure proper segregation during mitosis, chromosomes must be efficiently captured by spindle microtubules and subsequently aligned on the mitotic spindle. The efficacy of chromosome interaction with the spindle can be influenced by how widely chromosomes are scattered in space. Here, we quantify chromosome-scattering volume (CSV) and find that it is reduced soon after nuclear envelope breakdown (NEBD) in human cells. The CSV reduction occurs primarily independently of microtubules and is therefore not an outcome of interactions between chromosomes and the spindle. We find that, prior to NEBD, an acto-myosin network is assembled in a LINC complex-dependent manner on the cytoplasmic surface of the nuclear envelope. This acto-myosin network remains on nuclear envelope remnants soon after NEBD, and its myosin-II-mediated contraction reduces CSV and facilitates timely chromosome congression and correct segregation. Thus, we find a novel mechanism that positions chromosomes in early mitosis to ensure efficient and correct chromosome-spindle interactions.

Brachiobasilic arteriovenous fistula with superficialisation and transposition the basilic vein in a one stage surgical technique. Five years of single experience. / Fístulas arteriovenosas nativas humerobasílicas con superficialización y trasposición en un solo acto quirúrgico. Revisión de cinco años de experiencia.

BACKGROUND: The basilic vein is a deep vein which usually requires superficialisation and surgical transposition. MATERIAL AND METHODS: This is a retrospective study of 119 BBAVF-ST in patients with stage 5D chronic kidney disease who received an implant with a one-stage surgical technique (2011-2015). The percentage of primary (PP), assisted primary (APP) and secondary (SP) permeabilities were assessed, as well as the related complications. We analysed the permeabilities using Kaplan-Meier survival curves and a univariate Log Rank analysis (Mantel-Cox). P values less than or equal to 0.05 were considered as significant. RESULTS: The mean age of the study group was 67.9years, with 63.8% of the subjects being male. A total of 57 complications were detected during the follow-up period: 24 stenosis (42.1%), 11 thrombosis (19.2%), 7 vascular access steal syndromes (12.2%), 7 upper limb oedemas (12.2%), 6 post-puncture haematomas (10.5%) and 2 infections (3.5%). The percentages of PP obtained at 1, 6, 12 and 24months were 92.4%, 79.8%, 66.3% and 52%; APP: 94.1%, 87.3%, 80.4% and 65.6%, and SP: 95%, 89.1%, 84% and 67.5%, respectively. Diabetic patients presented with significantly worse permeabilities than vascular or idiopathic patients: (P=.037, .009 and .019, respectively). CONCLUSIONS: According to the results obtained in our study, the one-stage surgical implementation of BBAVF-ST presents high permeability rates and a small number of related complications. Diabetes mellitus is a factor related to a worse surgical prognosis. Some of the biggest advantages are the greater optimisation of health resources and a shorter time in which the central venous catheter needs to remain in the body.

O crime como ato perverso: uma análise das cartas de assassinos seriais / El crimen como un acto perverso: un análisis de cartas de asesinos en serie / Crime as a perverse act: analysis of letters from serial killers

RESUMO. Este trabalho se insere no campo teórico da psicanálise e tem por objetivo discutir, a partir do conceito de perversão, a relação entre o ato perverso e os assassinatos em série, através das comunicações que certos autores desse tipo de crime realizaram com a mídia e com as forças da lei. Para a realização desse objetivo foi feita uma análise de conteúdo, segundo Bardin (2011), em 35 cartas enviadas por sete assassinos em série diferentes para a grande mídia ou para a polícia. Como resultado, encontra-se o fato de que a estrutura desses documentos é bastante similar e apresentam descrições de seus crimes, seus estados mentais, além de ameaças à população e um deboche direcionado às autoridades e forças policiais. Por fim, nota-se que a estrutura do ato perverso, conforme pensada por Freud e Lacan, está presente nas cartas estudadas, que pertencem a épocas e lugares distintos, e cujos autores não tiveram contato direto entre si.

RESUMEN. Este trabajo es parte del campo teórico del psicoanálisis y tiene como objetivo identificar los comportamientos comunes que están presentes en diferentes actos perversos, más específicamente en las comunicaciones que los asesinos en serie llevan a cabo con los medios de comunicación y las fuerzas de la ley. Para lograr este objetivo, se realizó un análisis de contenido, según Bardin (2011) sobre 35 cartas enviadas por siete asesinos en serie diferentes a los principales medios de comunicación o la policía. Como resultado, existe el hecho de que la estructura de estos documentos es bastante similar y presenta descripciones de sus crímenes, sus estados mentales, además de las amenazas a la población y un libertinaje dirigido a las autoridades y las fuerzas policiales. Finalmente, se observa que la estructura del acto perverso, como lo piensan las teorías de Freud y Lacan, tiende a repetirse en los sujetos estudiados, que pertenecen a diferentes tiempos y lugares y que no tuvieron contacto directo entre sí.

ABSTRACT This work is part of the theoretical field of psychoanalysis and aims to discuss, from the concept of perversion, the relationship between the perverse act and serial murders, through the communications that certain authors of this type of crime made with the media and with the forces of the law. To achieve this objective, a content analysis was carried out, according to Bardin (2011), on thirty-five letters sent by seven different serial killers to the mainstream media or the police. As a result, there is the fact that the structure of these documents is quite similar and presents descriptions of their crimes, their mental states, in addition to threats to the population and a debauchery directed at the authorities and police forces. Finally, it is noted that the structure of the perverse act, as thought by the theories of Freud and Lacan, is present in the studied letters, which belong to different times and places, and whose authors had no direct contact with each other.

Adolescence With Freud and Flaubert. / La adolescencia con Freud y Flaubert.

The text approaches two fundamental aspects of the adolescent crisis from the works of Sigmund Freud and Gustave Flaubert: their encounter with their object in desire, pleasure, sexual act, and the causes the detachment from parental authority and their effects. A study was made on the work of Flaubert on the causes of the enigma, which the author suggests in his Memoirs of a Madman: Am I another or myself? That feeling of strangeness the adolescent experiences on waking up in a dream, with a new feeling and desire of the love object. The ardent desire of being like a grown-up, and the motions toward their parents, influence decisions for which the young are not prepared, given their cradled education and the unsatisfactory answers to their infant sexual investigation. Lacan notes that the sexual relationship does not exist. Freud rates love as being narcissistic and childish. The first amorous manifestations, given the fantasy that cloaks them always remain the same, as explained by Flaubert and Lacan's comment to Wedekind, in The Spring Awakening. In childhood the enjoyment of body is not involved. For this reason, it is so simple, the adolescent would be a representation of the division of the subject, the cut made by their unconscious, which their body, in certain cases, will carry the marks. They will be surprised, puzzled by this new desire that produces their unconscious to step toward the sexual act.

Quantitative Control of GPCR Organization and Signaling by Endocytosis in Epithelial Morphogenesis.

Tissue morphogenesis arises from controlled cell deformations in response to cellular contractility. During Drosophila gastrulation, apical activation of the actomyosin networks drives apical constriction in the invaginating mesoderm and cell-cell intercalation in the extending ectoderm. Myosin II (MyoII) is activated by cell-surface G protein-coupled receptors (GPCRs), such as Smog and Mist, that activate G proteins, the small GTPase Rho1, and the kinase Rok. Quantitative control over GPCR and Rho1 activation underlies differences in deformation of mesoderm and ectoderm cells. We show that GPCR Smog activity is concentrated on two different apical plasma membrane compartments, i.e., the surface and plasma membrane invaginations. Using fluorescence correlation spectroscopy, we probe the surface of the plasma membrane, and we show that Smog homo-clusters in response to its activating ligand Fog. Endocytosis of Smog is regulated by the kinase Gprk2 and ß-arrestin-2 that clears active Smog from the plasma membrane. When Fog concentration is high or endocytosis is low, Smog rearranges in homo-clusters and accumulates in plasma membrane invaginations that are hubs for Rho1 activation. Lastly, we find higher Smog homo-cluster concentration and numerous apical plasma membrane invaginations in the mesoderm compared to the ectoderm, indicative of reduced endocytosis. We identify that dynamic partitioning of active Smog at the surface of the plasma membrane or plasma membrane invaginations has a direct impact on Rho1 signaling. Plasma membrane invaginations accumulate high Rho1-guanosine triphosphate (GTP) suggesting they form signaling centers. Thus, Fog concentration and Smog endocytosis form coupled regulatory processes that regulate differential Rho1 and MyoII activation in the Drosophila embryo.

Cell-cell adhesion interface: rise of the lateral membrane.

The lateral membrane plays an important role in the mechanical stability of epithelial cell sheet in steady state. In addition, the lateral membrane is continuously remodeled during dynamic processes such as cell extrusion, cytokinesis, and intercellular cell movement. In wound healing, the lateral membrane must be built from flat and spread cells that had crawled into the area of the wound. Thus, forming the lateral membrane is a phenomenon that occurs not only in development but also during homeostatic maintenance and regeneration of differentiated epithelial tissues.

Structural Modeling of Mechanosensitivity in Non-Muscle Cells: Multiscale Approach to Understand Cell Sensing.

The contraction and spreading of nonmuscle cells are important phenomena in a number of cellular processes such as differentiation, morphogenesis, and tissue growth. Recent experimental work has shown that the topology and the mechanical properties of the underlying substrate play a significant role in directing the cell's response. In this work, we introduce a multiscale model to understand the sensing, activation, and contraction of the actin cytoskeleton of nonmuscle cells based on the idea that acto-myosin cross-bridges display a catch-bond response. After investigating the respective roles of bond catchiness and acto-myosin assembly on the mechano-sensitivity of stress fibers, we present full simulations of cells laying on arrays of micropillars. Model predictions show good qualitative agreements with experimental observation, suggesting that acto-myosin catch bonds are a major mechano-sensing element in nonmuscle cells.